Project Summary: This grant is a competitive renewal of our existing grant (DK-49302) and extends our investigative focus on the renin-angiotensin-aldosterone system (RAAS) in an independent direction, taking advantage of novel preliminary data derived from the existing grant demonstrating RAAS activation in HIV patients. We have shown that RAAS is a key hormone system which relates to critical cardiometabolic indices in HIV, providing a strong rationale for this proposal, and propose to study detailed endpoints on cardiac structure and function. Individuals with chronic HIV infection well-treated with antiretroviral therapy (ART) remain at significant risk for cardiovascular injury and dysfunction, and serious attention should be directed at the management of CVD risk reduction in HIV. Data provide support for the hypothesis that mineralocorticoid receptor (MR) activation contributes to inflammation and fibrosis in the heart and vasculature. Consistent with this hypothesis, our data demonstrate that HIV patients well-phenotyped for metabolic disease have increased RAAS activation and heightened inflammation under these conditions when compared to non-HIV individuals. Data also suggest that HIV patients demonstrate an increased prevalence of impaired coronary flow reserve, myocardial fibrosis, and coronary plaque?all clinically relevant complications of the coronary vasculature and myocardium associated with cardiovascular mortality. In this regard, no successful treatment strategies exist to complement ART to reduce CVD risk in HIV. To that end, we propose that treatment with a selective MR antagonist, eplerenone, for 12 months in a prospective randomized, double-blind, placebo controlled study will improve indices of the coronary vasculature and the myocardium when compared to placebo in HIV patients. This is a rational study, as our previous clinical studies have shown an effect of MR blockade on coronary flow reserve in the diabetes mellitus population, and preclinical evidence supports the effectiveness of MR blockade on inflammation, fibrosis and atherosclerosis. We will utilize sophisticated radiologic techniques to quantify baseline risk of coronary flow reserve, myocardial inflammation and fibrosis, and coronary plaque and assess longitudinal changes in these indices with MR blockade. Information regarding the natural history of these subtypes of CVD is limited among the HIV population, and thus, these studies will also inform us as to the progression of disease pathology in the coronary vasculature and myocardium in HIV. Furthermore, we will evaluate biomarkers of vascular dysfunction, inflammation, and fibrosis to understand the effects of MR blockade on these indices in relation to radiological assessment of cardiac structure and function. Moreover, these data will provide critical insight for other non-HIV populations with increased CVD burden. Our multidisciplinary team will combine expertise in metabolic dysregulation, cardiovascular endocrinology and imaging to conduct the first comprehensive investigation of MR blockade on CVD in HIV, which aims to provide novel mechanistic insight and a promising strategy for CVD risk reduction in HIV.